Exfoliation syndrome (XFS) is a common condition that causes high-tension open-angle glaucoma (XFG), pre- mature cataract formation, and complications during cataract surgery. Evidence suggests that XFS/XFG is genetically complex. LOXL1 is a major genetic risk factor for XFS/XFG, with LOXL1 variants occurring in up to 98% of patients. However, these same variants are also present in up to 80% of unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. Our goal is to comprehensively define risk factors (both genetic and environmental) for XFS/XFG, which will facilitate effective screening and prevention strategies and the development of novel therapies. In the previous funding period, using data from large ongoing prospective cohorts of Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS), we have identified major environmental exposures significantly influencing the risk of XFS/XFG including time spent outdoors, heavy coffee consumption and low dietary folate intake (related to elevated homocysteine). Using a case control sample from Mass Eye and Ear, we have assessed the contributions of CLU variants to XFS/XFG and have contributed to an international study identifying CACNA1A as a novel genetic risk factor. From 7 different US sites, we have collected DNA samples for 1241 XFS/XFG cases and genome-wide genotyping for both common and rare SNPs has been completed at CIDR. In NHS and HPFS, we project to have incident 600 cases of XFS/XFG among 100,000+ participants followed prospectively for 30+ years. For the next funding period, we propose the following specific aims: 1) complete genetic analyses to identify new genetic risk factors for XFS/XFG, including contributions of rare variants and explore complex genetic interactions; 2) investigate the role of environmental exposures related to homocysteine (DASH dietary pattern) and UV light exposure and explore interactions with LOXL1, and 3) complete the first pre-diagnostic metabolomic analysis for XFS/XFG focusing on metabolites related to homocysteine and folate and interactions for individual metabolites with LOXL1. This proposed research is significant because it is expected to advance and expand our understanding of the genetic etiology of XFS/XFG as it will leverage data from a large case/control study for genetic analyses and will be the first study of copy number variants and rare variants for this condition. The project is innovative in using prospectively collected environmental exposure data and pre-diagnostic serum for metabolomic studies in NHS/HPFS, to investigate factors present in cases prior to disease development. Overall these studies will advance our understanding of the predispoing events that could be therapeutic targets and biomarkers of disease risk.